title: Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome.
abstract: RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardio-facio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-RAF, MEK1, MEK2, and K-RAS. B-RAF is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-RafLSLV600E allele. This targeted allele allows low levels of expression of B-RafV600E, a constitutively active B-Raf kinase first identified in human melanoma. B-Raf+/LSLV600E mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf+/LSLV600E mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.
authors.affiliation: Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain.
authors.forename: Jelena
authors.initials: J
authors.lastname: Urosevic
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
authors.forename: María L
authors.initials: ML
authors.lastname: Soto-Montenegro
authors.forename: Santiago
authors.initials: S
authors.lastname: Reig
authors.forename: Manuel
authors.initials: M
authors.lastname: Desco
authors.forename: Emma M Burkitt
authors.initials: EM
authors.lastname: Wright
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004476:Ectodermal Dysplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004789:Enzyme Activation / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018358:Neuroendocrine Tumors / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism
chemical_list: C482128:MAP2K2 protein, human; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse